A study to determine the safety and maximum tolerable dose of LTI-01 in patients who has pneumonia-like symptoms with a build up of fluid in their lungs

• Register: ANZCTR
• Last refreshed on: 13 January 2020
• Main ID: ACTRN12616001442493
• Date of registration: 14/10/2016
• Prospective Registration: Yes
• Primary sponsor: Clinical Network Services Pty Ltd
• Public title: A study to determine the safety and maximum tolerable dose of LTI-01 in patients who has pneumonia-like symptoms with a build up of fluid in their lungs
• Scientific title: Phase 1a/1b Trial of LTI-01 (Single Chain Urokinase, scuPA) Intrapleural Fibrinolytic Therapy (IPFT) in Patients with Complicated Parapneumonic Effusions or Empyema
• Date of first enrolment: 07/03/2017
• Target sample size: 21
• Recruitment status: Stopped early
• URL: https://anzctr.org.au/ACTRN12616001442493.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Other;Type of endpoint: Safety/efficacy;
• Phase: Phase 1

Countries of recruitment

Australia, New Zealand

Contacts

• Name: Dr Steven Idell

• Name: Mr Brian Windsor

Key inclusion & exclusion criteria

Inclusion criteria: 1. Male or female greater than or equal to 21 years of age
2. A clinical presentation compatible with pneumonia and a parapneumonic effusion
3. Has pleural fluid requiring drainage that is loculated as determined by lateral decubitius or chest CT or by chest ultrasonography, and which is either:
* purulent or
* gram stain positive or
* culture positive or
* acidic with a pH <=7.2 or
* greater than half the volume of the thoracic cavity
.
4. Written informed consent
5. Failure to drain the pleural space within 3 h after tube thoracostomy
6. Hemodynamically stable and not requiring use of intravenous pressor therapy
7. Absence of severe metabolic derangements such as a serum potassium of <6 mEq/L or diabetic ketoacidosis
Exclusion criteria: 1. Previous treatment with intra-pleural fibrinolytics for this CPE/empyema
2. Has a known sensitivity to urokinase plasminogen activator
3. Has had a coincidental stroke, a major hemorrhage or major trauma
4. Head trauma or previous stroke
5. History of previous intracranial hemorrhage or symptoms suggestive of possible current intracranial hemorrhage.
6. Vascular puncture at a non-compressible site in the previous 7 days (e.g. subclavian artery, subclavian vein or internal jugular puncture)
7. Elevated blood pressure (systolic >185 mm Hg) or diastolic mm Hg (>110)
8. Active bleeding on examination
9. Acute bleeding diathesis: platelets <100,000 mm3 or therapeutic doses of heparin received within 48h or history of current warfarin therapy; use of other oral anticoagulants including warfarin or Xa or thrombin inhibitors.
10. Known platelet functional disorder or use of antiplatelet therapy including clopidigrel or other antiplatelet agents other than aspirin at any dose.
11. Estimated creatinine clearance of <30 ml/minute or estimated GFR (glomerular filtration rate)<30 ml/minute.
12. PT/PTT> 1.7x control or PT>15 sec.
13. Has had major surgery in the previous 10 days
14. Has had a previous pneumonectomy on the side of infection
15. Patients who are pregnant or lactating (females of childbearing potential must have a negative pregnancy test before randomization)
16. Expected survival less than three months from a different pathology to this empyema (e.g. metastatic lung carcinoma)
17. Known prior ipsilateral fibrothorax
18. Plasma fibrinogen (FGN) level < 150 mg/L
19. Known allergy to rodents

Age minimum: 21 Years
Age maximum: No limit
Gender: Both males and females

Health Condition(s) or Problem(s) studied

complicated parapneumonic effusions ;empyema;
complicated parapneumonic effusions
empyema

Respiratory - Other respiratory disorders / diseases

Intervention(s)

This is a prospective, open-label, dose escalation safety trial. Patients who present with symptoms consistent with pneumonia along with CPE/empyema will be initially treated by standard of care, including placement of chest tube and initiation of antibiotics, and will be evaluated for participation in this study. Eligible subjects will be appropriately consented to the study and will begin treatment with intrapleural LTI-01 within 24 hr of enrolment.

Subjects will be treated according to their assigned dose level daily for up to 3 days. First treatment will begin within 24 hours from initial consent. The study treatment will be administered as a bolus dose through the chest tube into the pleural space and allowed to stay in the space for 3 hours. This treatment will occur once per day for up to 3 consecutive days.

Study treatment will occur in a dose escalation format, with up to 5 dose level cohorts. The first 3 subjects enrolled will be given an initial dose of 50,000 IU LTI-01 daily for up to three days. Assuming there are no safety issues in these 3 subjects after review of safety data by the Safety Review Committee (SRC), comprising of the Medical Monitor, Study Investigators and the Sponsor, the dose level will be escalated (doubled) in each consecutive group of three subjects with dosing for up to three days at all dose levels. If complete resolution of the pleural process occurs after one or two doses of LTI-01 in any subject, no further LTI-01 will be administered. This escalation (three per dose level) will continue to a maximum dose level of 800,000 IU unless a dose limiting toxicity (DLT) is observed,

Clinical activity will be defined as pleural density improvement of 25%, (determined by the reduction of the percentage of pleural dens

Primary Outcome(s)

To evaluate the safety and tolerability of escalating doses of intrapleural LTI01.
This will be assessed as follows;
vital signs at 3, 5, 12, 18, 21 hours post dose, chest ultrasonography at 23 hours post each of the 3 doses, haematology, blood chemistry and plural fluid will be assessed at 3, and 23 hours post dose, assessment of PF drainage at 3 and 23 hours post dose and assessment of AE's and concomitant meds daily.[Maximum tolerated dose (MTD) will be assessed on Day 1 (dosing) to day 28 or hospital discharge. Which ever comes first.
Patient safety will be monitored continuously as above and MTD will be reached when two or more patients at a given cohort experience a dose limiting toxicity defined as either an acute bleeding event with more than 2mg per dL drop on blood Hgb with or without haemodynamic instability, or development of melena or overt bleeding from the chest tube including development of haemothorax with a pleural fluid Hct more than 50% that of blood Hct or a grade 3 non-haematological adverse event.]

Secondary Outcome(s)

efficacy assessment will include assessment of mortality this will be assessed by review of medical records at 3 and 12 months post last dose[this will be assessed throughout this hospitalisation and at 3 and 12 months post hospital discharge for this episode of CPE/empyema]

Efficacy assessment will include referral for surgery this will be assessed by review of the medical records[any time during this hospitalisation and at 3 and 12 months post hospital discharge for this episode of CPE/empyema]

To evaluate pharmacokinetic effects of escalating doses of intrapleural LTI-01 using surrogate measures on plasma samples by measuring scuPA antigen and activities, D-Dimer and fibrinogen levels.[This will be measured at 3 and 23 hours post each of the 3 doses]

Pleural space drainage will be measured to assess efficacy this will be assessed by review of chest ultrasounds[This will be assessed at 23 hours post each of the 3 doses]

To evaluate pharmacodynamic effects of escalating doses of intrapleural LTI-01 assessed using surrogate measures on pleural fluid samples by measuring scuPA antigen and activities, D-Dimer and fibrinogen levels.

[These will be measured at 3 and 23 hours post each of the 3 doses of LTI-01
]

efficacy assessment will include assessment of length of this hospitalisation this will be assed via review of medical records post discharge[this will be assessed throughout this hospitalisation for this episode of CPE/empyema]

Secondary ID(s)

Nil known

Source(s) of Monetary Support

Lung Therapeutics, Inc

Secondary Sponsor(s)

Lung Therapeutics, Inc

Ethics review

Status: Approved
Approval date:
Contact:

Northern B Health and Disability Ethics Committee

Status: Approved
Approval date:
Contact:

Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee

Status: Approved
Approval date:
Contact:

Western Sydney Local Health District Human Research Ethics Committee